Recellularization and Integration of Dense Extracellular Matrix by Percolation of Tissue Microparticles

Cells embedded in the extracellular matrix of tissues play a critical role in maintaining homeostasis while promoting integration and regeneration following damage or disease. Emerging engineered biomaterials utilize decellularized extracellular matrix as a tissue-specific support structure; however, many dense, structured biomaterials unfortunately demonstrate limited formability, fail to promote cell migration, and result in limited tissue repair. Here, a reinforced composite material of densely packed acellular extracellular matrix microparticles in a hydrogel, termed tissue clay, that can be molded and crosslinked to mimic native tissue architecture is developed. Hyaluronic acid-based hydrogels are utilized, amorphously packed with acellular cartilage tissue particulated to ≈125–250 microns in diameter and defined a percolation threshold of 0.57 (v/v) beyond which the compressive modulus exceeded 300 kPa. Remarkably, primary chondrocytes recellularize particles within 48 h, a process driven by chemotaxis, exhibit distributed cellularity in large engineered composites, and express genes consistent with native cartilage repair. In addition, broad utility of tissue clays through recellularization and persistence of muscle, skin, and cartilage composites in an in vivo mouse model is demonstrated. The findings suggest optimal material architectures to balance concurrent demands for large-scale mechanical properties while also supporting recellularization and integration of dense musculoskeletal and connective tissues.     

Microstructure‐sensitive fatigue modelling of medical‐grade fine wire

This work presents a modelling methodology to assess the sensitivity to microstructure in high‐cycle fatigue performance of fine wires made from MP35N alloy (35Ni‐35Co‐20Cr‐10Mo in wt%) used as conductors in cardiac leads. The model consists of a microstructure generator that creates a mesh of a statistically representative microstructure, a finite element analysis using a crystal plasticity constitutive model to determine the local response behaviour of the microstructure, and a postprocesser using fatigue indicating parameters to assess the likelihood of fatigue crack initiation. The fatigue crack initiation potency for selected microstructure attributes, boundary and interface conditions, and loading profiles is determined by computing the Fatemi‐Socie fatigue indicating parameter over a physically relevant volume of scale. Case studies are used to investigate (1) the influence of nonmetallic inclusion proximity to the wire surface on fatigue potency and (2) the transition life demarcating lives primarily controlled by fatigue crack initiation versus microcrack fatigue growth.     

Transition modelling of surface flaws to through cracks

Cracks starting at surfaces will grow under fatigue loading conditions both along the surface and in the thickness directions of the component geometry. In those cases where the crack grows through the thickness, the fatigue crack may transition to a corresponding through crack geometry. While the fatigue crack growth behaviour of both the surface flaws and complete through cracks are well understood, the method for modelling the process by which they transition from one to the other is not. This paper seeks to bring greater clarity and understanding to the transition process by implementing a transition method and developing the associated codes and equations to do so based on careful consideration of boundary conditions, experimental data, and finite element simulations.     

Enteral glutamine supplementation for very-low-birth-weight infants decreases hospital costs

Vertebrate Pax-6 and its Drosophila homolog eyeless play central roles in eye specification, although it is not clear if this represents the ancestral role of this gene class. As the most "primitive" animals with true nervous systems, the Cnidaria may be informative in terms of the evolution of the Pax gene family. For this reason we surveyed the Pax gene complement of a representative of the basal cnidarian class (the Anthozoa), the coral Acropora millepora. cDNAs encoding two coral Pax proteins were isolated. Pax-Aam encoded a protein containing only a paired domain, whereas Pax-Cam also contained a homeodomain clearly related to those in the Pax-6 family. The paired domains in both proteins most resembled the vertebrate Pax-2/5/8 class, but shared several distinctive substitutions. As in most Pax-6 homologs and orthologs, an intron was present in the Pax-Cam locus at a position corresponding to residues 46/47 in the homeodomain. We propose a model for evolution of the Pax family, in which the ancestor of all of the vertebrate Pax genes most resembled Pax-6, and arose via fusion of a Pax-Aam-like gene (encoding only a paired domain) with an anteriorly-expressed homeobox gene resembling the paired-like class.     

Mechanisms and Microenvironment Investigation of Cellularized High Density Gradient Collagen Matrices via Densification

Biological tissues and biomaterials are often defined by unique spatial gradients in physical properties that impart specialized function over hierarchical scales. The structure of these materials forms continuous transitional gradients and discrete local microenvironments between adjacent (or within) tissues, and across matrix–cell boundaries, which is difficult to replicate with common scaffold systems. Here, the matrix densification of collagen leading to gradients in density, mechanical properties, and fibril morphology is studied. High‐density regions form via a fluid pore pressure and flow‐driven mechanism, with increased relative fibril density (10×), mechanical properties (20×, to 94.40 ± 18.74 kPa), and maximum fibril thickness (1.9×, to >1 μm) compared to low‐density regions, while maintaining porosity and fluid/mass transport to support viability of encapsulated cells. Similar to the organization of the articular cartilage zonal structure, it is found that high‐density collagen regions induce cell and nuclear alignment of primary chondrocytes. Chondrocyte gene expression is maintained in collagen matrices, and no phenotypic changes are observed as a result of densification. Collagen densification provides a tunable platform for the creation of gradient systems to study complex cell–matrix interactions. These methods are easily generalized to compression and boundary condition modalities useful to mimic a broad range of tissues.